Submission Details
Molecule(s):
COc1cc2c(NC(=O)Cc3cccc(Cl)c3)cncc2cn1
COc1cc2cncc(NC(=O)Cc3cccc(Cl)c3)c2cn1
COc1cc2c(NC(=O)[C@@H]3CCOc4ccc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@@H]3CCOc4ccc(Cl)cc43)c2cn1
PET-UNK-f4e47ebd-5
Duplicate of:
EDJ-MED-611d11e7-12
O=C(Nc1cncc2ccncc12)[C@@H]1CCOc2cc(F)c(Cl)cc21
O=C(Nc1cncc2cnccc12)[C@@H]1CCOc2cc(F)c(Cl)cc21
COc1cc2c(NC(=O)[C@@H]3CCOc4cc(F)c(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@@H]3CCOc4cc(F)c(Cl)cc43)c2cn1
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3ccncc23)C1
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cnccc23)C1
COc1cc2c(NC(=O)[C@@H]3CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@@H]3CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)c2cn1
CS(=O)(=O)N1Cc2cc(F)c(Cl)cc2[C@H](C(=O)Nc2cncc3ccncc23)C1
CS(=O)(=O)N1Cc2cc(F)c(Cl)cc2[C@H](C(=O)Nc2cncc3cnccc23)C1
COc1cc2c(NC(=O)[C@@H]3CN(S(C)(=O)=O)Cc4cc(F)c(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@@H]3CN(S(C)(=O)=O)Cc4cc(F)c(Cl)cc43)c2cn1
PET-UNK-f4e47ebd-17
Duplicate of:
EDJ-MED-611d11e7-10
CO[C@@]1(C(=O)Nc2cncc3ccncc23)CCOc2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CCOc4ccc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@]3(OC)CCOc4ccc(Cl)cc43)c2cn1
CO[C@@]1(C(=O)Nc2cncc3ccncc23)CCOc2cc(F)c(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnccc23)CCOc2cc(F)c(Cl)cc21
COc1cc2cncc(NC(=O)[C@]3(OC)CCOc4cc(F)c(Cl)cc43)c2cn1
COc1cc2c(NC(=O)[C@]3(OC)CCOc4cc(F)c(Cl)cc43)cncc2cn1
CO[C@@]1(C(=O)Nc2cncc3cnccc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccncc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@]3(OC)CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)c2cn1
CO[C@@]1(C(=O)Nc2cncc3cnccc23)CN(S(C)(=O)=O)Cc2cc(F)c(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccncc23)CN(S(C)(=O)=O)Cc2cc(F)c(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CN(S(C)(=O)=O)Cc4cc(F)c(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@]3(OC)CN(S(C)(=O)=O)Cc4cc(F)c(Cl)cc43)c2cn1
Design Rationale:
Aza-substitution of the P1-isoquinoline leads to loss of potency and two factors may contribute. First, competition for electron density between the two Ns of the heterocyclic system reduces the capacity of each to accept a hydrogen bond. Second, binding to target will compromise the solvation of the aza-substituent even though it is partially accessible to solvent. Methoxy next to the aza-substituent is expected to weaken it as a hydrogen bond acceptor (pKBHX values for pyridine and 2-methoxypyridine are 1.86 and 0.99 respectively) which would reduce the desolvation penalty. Methoxy would be expected strengthen the isoquinoline nitrogen as a hydrogen bond acceptor (potentially offsetting the effect of aza-substitution on hydrogen bond acceptor strength) and the effect should be greater at C6 than at C7 (pKa values of 6-aminoisoquinoline and 7-aminoisoquinoline are 7.2 and 6.2 respectively; see https://doi.org/10.1021/jo00972a031 ). I would expect the 6-methoxy, 7-aza disubstitution to work better than the 6-aza, 7-methoxy disubstitution and believe that the hypothesis can be adequately tested with Design 1 and Design 2 (6-methoxy is well tolerated for isoquinoline, both parent naphthyridines have already been assayed and there is no chiral center). While designs for different scaffolds (in case these are of interest to the design team) have been included, my recommendation is to synthesize Design 1 and Design 2 in the first instance.
Other Notes:
The submission consists of designs with 6-methoxy-2,7-naphthyridine or 7-methoxy-2,6-naphthyridine at P1 and parent naphthyridines have included in the submission if they have not been already registered. Protein-ligand complexes were energy minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The X11612 A chain was used for modelling designs 1-16 and the P0157 A chain was used for modelling designs 5-8. The PDB file associated with this submission contains the following: [1] X11612 A chain [2] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3-18] Designs 1-16 [19] P0157 A chain [20] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [21-35] Designs 17-32